Target of HIV-1 Envelope Glycoprotein gp120–Induced Hippocampal Neuron Damage: Role of Voltage-Gated K⁺ Channel Kv2.1

Abstract

Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120) has been reported to be toxic to the hippocampal neurons, and to be involved in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Accumulating evidence has demonstrated that voltage-gated potassium (Kv) channels, especially the outward delayed-rectifier K(+) (Ik) channels, play a critical role in gp120-induced cortical neuronal death in vitro. However, the potential mechanisms underlying the hippocampal neuronal injury resulted from gp120-mediated neurotoxicity remain poorly understood. Using whole-cell patch clamp recording in cultured hippocampal neurons, this study found that gp120 significantly increased the outward delayed-rectifier K(+) currents (Ik). Meanwhile, Western blot assay revealed that gp120 markedly upregulated Kv2.1 protein levels, which was consistent with the increased Ik density. With Western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling assays, it was discovered that gp120-induced neuronal injury was largely due to activation of Kv2.1 channels and resultant apoptosis mediated by caspase-3 activation, as the pharmacological blockade of Kv2.1 channels largely attenuated gp120-induced cell damage and caspase-3 expression. Moreover, p38 MAPK was demonstrated to participate in gp120-induced hippocampal neural damage, since p38 MAPK antagonist (SB203580) partially abrogated gp120-induced Kv2.1 upregulation and neural apoptosis. Taken together, these results suggest that gp120 induces hippocampal neuron apoptosis by enhancement of the Ik, which might be associated with increased Kv2.1 expression via the p38 MAPK pathway.

Involvement of the delayed rectifier outward potassium channel Kv2.1 in methamphetamine‐induced neuronal apoptosis via the p38 mitogen‐activated protein kinase signaling pathway

“…The increased Kv2.1 expression is associated with cell injury (Zhu et al, ). Therefore, we first sought to investigate whether the Meth treatment affects Kv2.1 expression.…”

“…Kv2.1 contributes the majority of delayed rectifier K + currents (I DR ) in mammalian brain neurons and is a key regulator of intrinsic neuronal excitability (Du, Haak, Phillipstansey, Russell, & McBain, ; Malin & Nerbonne, ; Mohapatra & Trimmer, ) and a modulator of apoptotic programs associated with oxidative stress (Sesti, Wu, & Liu, ). The results of our previous study indicated that gp120, one of the HIV envelope glycoproteins, significantly activated Kv2.1, which contributed to K + efflux and finalized neural apoptosis (Zhu et al, ). Based on the previous characterization of Meth‐induced cytotoxicity, and the essential nature of the potassium channel in the apoptotic process, we sought to determine the role of Kv2.1 in neuronal injury caused by Meth and the underlying signaling pathways.…”

Voltage-Gated Potassium Channels as Regulators of Cell Death

“…Its envelope glycoprotein gp120 has been associated to the pathogenesis of HIV-1-associated neurodegenerative disorders by acting on Kv2.1. In hippocampal neurons, gp120 was shown to increase Kv2.1 expression and current density in a p38- and caspase-3-dependent manner, thus enhancing apoptosis ( Shepherd et al, 2012 , 2013 ; Liu et al, 2013 ; Zhu et al, 2015 ). p38 plays a role also in methamphetamine-induced neuronal damage.…”

Involvement of purinergic 2X4 receptor in glycoprotein 120‐induced pyroptosis in dorsal root ganglia

“…One of the primary pathogens for neuronal injury and death in HAND patients was the HIV-1 envelope glycoprotein 120 (gp120) (Major et al 2000;Antinori et al 2007;Portegies et al, 2011). Gp120 may interact with the cell surface receptors present on neurons, triggering inflammatory responses or aggravating inflammatory responses to cause neuronal injury (Rao et al 2014;Xia et al 2015;Zhu et al 2015).…”